Our objective is to understand the regulatory mechanisms that control the proliferation, differentiation and apoptosis of hematopoietic cells and how oncoproteins subvert these mechanisms to cause leukemia The focus in this proposal is on two growth factor receptor tyrosine kinases (RTK) that have been implicated in the development of leukemia. The Sea/Stk/Ron receptor has been implicated in the development of multiple myeloma. Leukemia involves the loss of regulatory mechanisms that control the balance between cell growth, apoptosis and differentiation. Based on precedent, RTKs have the potential to affect all three of these regulatory mechanisms. Our aims are to determine (i) which regulatory events are disrupted by the Sea/Stk/Ron and FGFR3 receptors in erythroid leukemia and multiple myeloma, and (ii) to identify the contributions of the various signaling cascades in these events. We will utilize a novel murine erythroid cell system into which we will introduce various versions of the Sea/Stk/Ron receptors to determine how they affect the growth, apoptosis and differentiation of erythroid cells. We will identify the signal transduction pathways that are activated. By interfering with these pathways and using erythroid cells from mice genetically null for proteins in these pathways, we will identify the regulatory events controlled by the individual pre-B cells engineered to express FGFR3 to determine to determine how this receptor alters their growth, apoptosis and differentiation and contributes to the myeloma phenotype. We will identify the different signal transduction pathways that are activated in pre-B cells and determine how these pathways control leukemic development and progression. Finally, we will test multiple myeloma cell lines that express FGFR3 due to chromosomal translocations to determine if FGFR3 signaling has similar biological consequences in human leukemic cells.